Assessing the profile and utility of diplomates in occupational medicine.

BACKGROUND: The utility of the occupational medicine diploma in the UK is yet to be explored. The NHS 'Growing Occupational Health (OH) and Wellbeing' programme provides opportunities for diplomates to increase their OH work. AIMS: To assess what proportion of diplomates carry out OH work, the type of work being undertaken, to identify obstacles impeding OH work, to capture their interest in future work opportunities and what additional support they require. METHODS: A link to an online questionnaire was sent to diplomates via several professional bodies; we estimate that 2428 diplomates received this. The survey was open from 24 March to 31 May 2022. RESULTS: Replies were received from 310/2428 (13%) diplomates. Fifty-two per cent of respondents were males and 35% were female. Respondents were diverse in terms of age and geographical region. Main employment settings: 13% primary care, 43% secondary care, 31% private sector, 24% public sector and 20% self-employed. Seventy-two per cent of diplomates had undertaken OH clinical work since completion of their diploma, and 90% of those were undertaking OH clinical work at the time of the survey. Specific obstacles to accessing OH work highlighted included existing workload constraints, lack of employment opportunities with OH providers and lack of time. CONCLUSIONS: Many (126/310; 41%) respondents had considered increasing their OH work in the previous 12 months. Increasing mentorship from senior OH clinicians to diplomates was suggested by 4% of respondents to enhance the utility of diplomates.

Patient preferences for the treatment of chronic cough: a discrete choice experiment.

BACKGROUND: Chronic cough is common, negatively affects quality of life and has limited treatment options. Inhibition of purinergic signalling is a promising therapeutic approach but is associated with taste-related adverse effects. Little is known about treatment preferences from the perspective of patients with chronic cough, such as trade-offs between efficacy and side effect. METHODS: Patients with chronic cough completed an online discrete choice experiment survey in which they answered a series of questions requiring a choice between two constructed treatment options characterised by varying attribute levels. Selection of cough and taste-related attributes was informed by qualitative interviews and clinical trial data. Logit-based models were used to analyse resulting choice data. RESULTS: The discrete choice experiment survey was completed by 472 participants with chronic cough. Among study attributes, frequency of intense cough attacks was the most important to participants, followed by taste change, frequency of night-time coughing and frequency of daytime coughing. To accept the least preferred taste disturbance of a bitter, metallic, chalky or oily taste change, participants required either: (1) elimination of night-time cough along with a slight reduction in daytime cough; (2) elimination of daytime cough along with a pronounced reduction in night-time or (3) reduction in intense cough attacks from 7 to 2 times per week. Two distinct preference patterns were identified, each placing different importance on efficacy versus side effect trade-offs. CONCLUSIONS: Participants with chronic cough were willing to accept some taste disturbances in exchange for improved efficacy of chronic cough treatments. Knowledge of patient preferences can facilitate shared decision-making.

Specific pathway abundances in the neonatal calf faecal microbiome are associated with susceptibility to Cryptosporidium parvum infection: a metagenomic analysis.

BACKGROUND: Cryptosporidium parvum is the main cause of calf scour worldwide. With limited therapeutic options and research compared to other Apicomplexa, it is important to understand the parasites' biology and interactions with the host and microbiome in order to develop novel strategies against this infection. The age-dependent nature of symptomatic cryptosporidiosis suggests a link to the undeveloped immune response, the immature intestinal epithelium, and its associated microbiota. This led us to hypothesise that specific features of the early life microbiome could predict calf susceptibility to C. parvum infection. RESULTS: In this study, a single faecal swab sample was collected from each calf within the first week of life in a cohort of 346 animals. All 346 calves were subsequently monitored for clinical signs of cryptosporidiosis, and calves that developed diarrhoea were tested for Rotavirus, Coronavirus, E. coli F5 (K99) and C. parvum by lateral flow test (LFT). A retrospective case-control approach was taken whereby a subset of healthy calves (Control group; n = 33) and calves that went on to develop clinical signs of infectious diarrhoea and test positive for C. parvum infection via LFT (Cryptosporidium-positive group; n = 32) were selected from this cohort, five of which were excluded due to low DNA quality. A metagenomic analysis was conducted on the faecal microbiomes of the control group (n = 30) and the Cryptosporidium-positive group (n = 30) prior to infection, to determine features predictive of cryptosporidiosis. Taxonomic analysis showed no significant differences in alpha diversity, beta diversity, and taxa relative abundance between controls and Cryptosporidium-positive groups. Analysis of functional potential showed pathways related to isoprenoid precursor, haem and purine biosynthesis were significantly higher in abundance in calves that later tested positive for C. parvum (q ≤ 0.25). These pathways are either absent or streamlined in the C. parvum parasites. Though the de novo production of isoprenoid precursors, haem and purines are absent, C. parvum has been shown to encode enzymes that catalyse the downstream reactions of these pathway metabolites, indicating that C. parvum may scavenge those products from an external source. CONCLUSIONS: The host has previously been put forward as the source of essential metabolites, but our study suggests that C. parvum may also be able to harness specific metabolic pathways of the microbiota in order to survive and replicate. This finding is important as components of these microbial pathways could be exploited as potential therapeutic targets for the prevention or mitigation of cryptosporidiosis in bovine neonates.

Impacts of radiation exposure, hindlimb unloading, and recovery on murine skeletal muscle cell telomere length.

Astronauts are exposed to harsh conditions, including cosmic radiation and microgravity. Spaceflight elongates human telomeres in peripheral blood, which shorten upon return to Earth and approach baseline levels during postflight recovery. Astronauts also encounter muscle atrophy, losing up to 20% loss of muscle mass on spaceflights. Telomere length changes in muscle cells of astronauts remain unexplored. This study investigates telomere alterations in grounded mice experiencing radiation exposure and muscle atrophy, via a hindlimb unloading spaceflight mimicking model. We find telomere lengthening is present in muscle stem cells and in myofiber nuclei, but not in muscle-resident endothelial cells. We further assessed telomere length in the model following hindlimb unloading recovery. We find that telomere length failed to return to baseline values. Our results suggest a role for telomeres in muscle acclimatization, which is relevant for the well-being of astronauts in space, and upon their return to Earth.

Telomeric DNA breaks in human induced pluripotent stem cells trigger ATR-mediated arrest and telomerase-independent telomere damage repair.

Although mechanisms of telomere protection are well-defined in differentiated cells, it is poorly understood how stem cells sense and respond to telomere dysfunction. In particular, the broader impact of telomeric double-strand breaks (DSBs) in these cells is poorly characterized. Here, we report on DNA damage signaling, cell cycle, and transcriptome-level changes in human induced pluripotent stem cells (iPSCs) in response to telomere-internal DSBs. We engineered human iPSCs with an inducible TRF1-FokI fusion protein to acutely induce DSBs at telomeres. Using this model, we demonstrate that TRF1-FokI DSBs activate an ATR-dependent DDR, which leads to p53-independent cell cycle arrest in G2. Using CRISPR-Cas9 to cripple the catalytic domain of telomerase, we show that telomerase is largely dispensable for survival and lengthening of TRF1-FokI-cleaved telomeres, which instead are effectively repaired by robust homologous recombination (HR). In contrast to HR-based telomere maintenance in mouse embryonic stem cells, we find neither evidence that HR causes extension of telomeres beyond their initial lengths, nor an apparent role for ZSCAN4 in this process. Rather, HR-based repair of telomeric breaks is sufficient to maintain iPSC telomeres at a normal length which is compatible with sustained survival of the cells over several days of TRF1-FokI induction. Our findings suggest a previously unappreciated role for HR in telomere maintenance in telomerase-positive iPSCs and reveal distinct iPSC-specific responses to targeted telomeric damage.

Critical analysis of the term sport by José María Cagigal / Análisis crítico del término deporte de José María Cagigal

The intellectual heritage of modernity has not contributed to the development of philosophical thinking about sport. However, there have been personalities who have interpreted sport from a deeper perspective than what common sense would suggest. One of them was José María Cagigal, pedagogue and philosopher representing the international Olympic movement and Physical Education in Spain. This essay analysed the ideas of this thinker in relation to his concept of sport. In this way, it was possible to identify an interpretation aimed at extending cultural and epistemological boundaries. This promoted meaningwith ambiguity and relativity between the contemporary distinction of physical activity, physical exercise, play and sport. Nevertheless, it is appreciated that Cagigal's thinking has the potential to avoid reductionisms around universal definitions of sporting activity that can be established (AU)

La herencia intelectualdela modernidad no ha contribuidoa que el pensamiento filosófico del deporte haya podidoser muy desarrollado. Sin embargo, han existidopersonalidades que haninterpretadoel deporte desde una mirada más profunda que laque propiciabael sentido común. Una de ellas fue la de José María Cagigal, pedagogo y filósofo representante del movimiento olímpico internacional y de la Educación Física en España. Este ensayo analizó las ideas de aquel pensador en torno a su concepto de deporte. De este modo, se logró identificar una interpretación orientada a ampliar las fronteras culturales y epistemológicas. Estopromovió significados con ambigüedad y relatividad entre la distinción contemporánea de actividad física, ejercicio físico, juego y deporte. No obstante, se aprecia que el pensamiento de Cagigal tiene potencial para evitar reduccionismos en torno a las definiciones universales que se puedan establecer de la actividad deportiva (AU)

APC and P53 mutations synergise to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer.

OBJECTIVE: Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with the majority of cases initiated by inactivation of the APC tumour suppressor. This results in the constitutive activation of canonical WNT pathway transcriptional effector ß-catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM which antagonises WNT-FZD receptor-ligand interactions. Here, we sought to evaluate the effects of NOTUM activity on CRC as a function of driver mutation landscape. DESIGN: Mouse and human colon organoids engineered with combinations of CRC driver mutations were used for Notum genetic gain-of-function and loss-of-function studies. In vitro assays, in vivo endoscope-guided orthotopic organoid implantation assays and transcriptomic profiling were employed to characterise the effects of Notum activity. Small molecule inhibitors of Notum activity were used in preclinical therapeutic proof-of-principle studies targeting oncogenic Notum activity. RESULTS: NOTUM retains tumour suppressive activity in APC-null adenomas despite constitutive ß-catenin activity. Strikingly, on progression to adenocarcinoma with P53 loss, NOTUM becomes an obligate oncogene. These phenotypes are Wnt-independent, resulting from differential activity of NOTUM on glypican 1 and 4 in early-stage versus late-stage disease, respectively. Ultimately, preclinical mouse models and human organoid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonisation of distal organs. CONCLUSIONS: Our findings that a single agent targeting the extracellular enzyme NOTUM is effective in treating highly aggressive, metastatic adenocarcinomas in preclinical mouse models and human organoids make NOTUM and its glypican targets therapeutic vulnerabilities in advanced CRC.

Patient-Induced Pluripotent Stem Cell-Derived Hepatostellate Organoids Establish a Basis for Liver Pathologies in Telomeropathies.

BACKGROUND & AIMS: Dyskeratosis congenita (DC) is a telomere biology disorder caused primarily by mutations in the DKC1 gene. Patients with DC and related telomeropathies resulting from premature telomere dysfunction experience multiorgan failure. In the liver, DC patients present with nodular hyperplasia, steatosis, inflammation, and cirrhosis. However, the mechanism responsible for telomere dysfunction-induced liver disease remains unclear. METHODS: We used isogenic human induced pluripotent stem cells (iPSCs) harboring a causal DC mutation in DKC1 or a CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9)-corrected control allele to model DC liver pathologies. We differentiated these iPSCs into hepatocytes (HEPs) or hepatic stellate cells (HSCs) followed by generation of genotype-admixed hepatostellate organoids. Single-cell transcriptomics were applied to hepatostellate organoids to understand cell type-specific genotype-phenotype relationships. RESULTS: Directed differentiation of iPSCs into HEPs and stellate cells and subsequent hepatostellate organoid formation revealed a dominant phenotype in the parenchyma, with DC HEPs becoming hyperplastic and also eliciting a pathogenic hyperplastic, proinflammatory response in stellate cells independent of stellate cell genotype. Pathogenic phenotypes in DKC1-mutant HEPs and hepatostellate organoids could be rescued via suppression of serine/threonine kinase AKT (protein kinase B) activity, a central regulator of MYC-driven hyperplasia downstream of DKC1 mutation. CONCLUSIONS: Isogenic iPSC-derived admixed hepatostellate organoids offer insight into the liver pathologies in telomeropathies and provide a framework for evaluating emerging therapies.

How Much Better is Faster? Value Adjustments for Health-Improvement Sequences.

While the quality-adjusted life-year construct has advantages of simplicity and consistency, simplicity requires strong assumptions. In particular, standard assumptions result in health-state utility functions that are unrealistically linear and separable in risk and duration. Consequently, sequencing of a series of health improvements has no effect on the total value of the sequence because each increment is assessed independently of previous increments. Utility functions in nearly all other areas of applied economics are assumed to be nonlinear with diminishing marginal utility so it matters where an improvement occurs in a sequence. We construct a conceptual framework that that demonstrates how diminishing marginal utility for health improvements could affect preferences for different sequence patterns. Using this framework, we derive conditions for which the sum of conventional health-state utilities understates, overstates, or approximates the sequence-sensitive value of health improvements. These patterns suggest the direction and magnitude of possible adjustments to conventional value calculations. We provide numerical examples and identify recent studies whose results are consistent with the conceptual model.

Patient-Preference Diagnostics: Adapting Stated-Preference Methods to Inform Effective Shared Decision Making.

BACKGROUND: While clinical practice guidelines underscore the need to incorporate patient preferences in clinical decision making, incorporating meaningful assessment of patient preferences in clinical encounters is challenging. Structured approaches that combine quantitative patient preferences and clinical evidence could facilitate effective patient-provider communication and more patient-centric health care decisions. Adaptive conjoint or stated-preference approaches can identify individual preference parameters, but they can require a relatively large number of choice questions or simplifying assumptions about the error with which preferences are elicited. METHOD: We propose an approach to efficiently diagnose preferences of patients for outcomes of treatment alternatives by leveraging prior information on patient preferences to generate adaptive choice questions to identify a patient's proximity to known preference phenotypes. This information can be used for measuring sensitivity and specificity, much like any other diagnostic procedure. We simulated responses with varying levels of choice errors for hypothetical patients with specific preference profiles to measure sensitivity and specificity of a 2-question preference diagnostic. RESULTS: We identified 4 classes representing distinct preference profiles for patients who participated in a previous first-time anterior shoulder dislocation (FTASD) survey. Posterior probabilities of class membership at the end of a 2-question sequence ranged from 87% to 89%. We found that specificity and sensitivity of the 2-question sequences were robust to respondent errors. The questions appeared to have better specificity than sensitivity. CONCLUSIONS: Our results suggest that this approach could help diagnose patient preferences for treatments for a condition such as FTASD with acceptable precision using as few as 2 choice questions. Such preference-diagnostic tools could be used to improve and document alignment of treatment choices and patient preferences. HIGHLIGHTS: Approaches that combine patient preferences and clinical evidence can facilitate effective patient-provider communication and more patient-centric healthcare decisions. However, diagnosing individual-level preferences is challenging, and no formal diagnostic tools exist.We propose a structured approach to efficiently diagnose patient preferences based on prior information on the distribution of patient preferences in a population.We generated a 2-question test of preferences for the outcomes associated with the treatment of first-time anterior shoulder dislocation.The diagnosis of preferences can help physicians discuss relevant aspects of the treatment options and proactively address patient concerns during the clinical encounter.

How Does the Public Evaluate Vaccines for Low-Incidence, Severe-Outcome Diseases? A General-Population Choice Experiment.

BACKGROUND: Because immunizing large numbers of healthy people could be required to reduce a relatively small number of infections, disease incidence has a large impact on cost effectiveness, even if the infection is associated with very serious health outcomes. In addition to cost effectiveness, the US Advisory Committee on Immunization Practices requires evidence of stakeholders' values and preferences to help inform vaccine recommendations. This study quantified general-population preferences for vaccine trade-offs among disease severity, disease incidence, and other vaccine features. METHODS: We developed a best-practice discrete choice experiment survey and administered it to 1185 parents of children aged 12-23 years and 1203 young adults aged 18-25 years from a national opt-in consumer panel. The data were analyzed using exploded-logit latent-class analysis. RESULTS: Latent-class analysis identified two classes with similar relative-importance weights in both samples. One of the two classes represented about half the samples and had preferences consistent with well-structured, logically ordered, and acceptably precise stated-preference utility. Preferences for the other half of the samples were poorly defined over the ranges of vaccine and disease attributes evaluated. Both parents and young adults in the first class evaluated protection from a disease with 1 in 100 incidence and full recovery at home as having statistically the same preference utility as a disease with 1 in 1 million incidence requiring hospitalization and resulting in permanent deafness. CONCLUSIONS: The results suggest that vaccines that protect against low-incidence, severe-outcome diseases, provide 'peace of mind' benefits not captured by standard health-outcome metrics. The fact that half the respondents had poorly defined vaccine preferences is a reminder of the challenges of implementing patient-centric vaccine decision making.

Associations between shortened telomeres and rheumatoid arthritis-associated interstitial lung disease among U.S. Veterans.

BACKGROUND: Shortened telomeres are associated with several different subtypes of interstitial lung disease (ILD), although studies of telomere length and ILD in rheumatoid arthritis (RA) are lacking. METHODS: Within the Veterans Affairs Rheumatoid Arthritis (VARA) registry, we performed cross-sectional and case-control studies of prevalent and incident ILD, respectively. We randomly selected a subset of RA patients with ILD and individually matched them to RA patients without ILD according to age, sex, and VARA enrollment date. Telomere length was measured on peripheral blood leukocytes collected at registry enrollment using quantitative PCR (T/S ratio). Short telomeres were defined as a T/S ratio in the lowest 10th percentile of the cohort. RESULTS: Our cross-sectional study cohort was comprised of 54 RA-ILD patients and 92 RA-non-ILD patients. T/S ratios significantly differed between patients with and without prevalent ILD (1.56 [IQR 1.30, 1.78] vs. 1.96 [IQR 1.65, 2.27], p < 0.001). Similarly, prevalence of ILD was significantly higher in patients with short vs. normal-length telomeres (73.3% vs. 32.8%, p = 0.002). Short telomeres were independently associated with an increased odds of prevalent ILD compared to normal-length telomeres (adjusted OR 6.60, 95% CI 1.78-24.51, p = 0.005). In our case-control analysis, comprised of 22 incident RA-ILD cases and 36 RA-non-ILD controls, short telomeres were not associated with incident RA-ILD (adjusted OR 0.90, 95% CI 0.06-13.4, p = 0.94). CONCLUSION: Short telomeres were strongly associated with prevalent but not incident ILD among patients with RA. Additional studies are needed to better understand telomere length dynamics among RA patients with and without ILD.

Remote sensing to detect harmful algal blooms in inland waterbodies.

Harmful algal blooms (HABs) are an issue of concern for water management worldwide. As such, effective monitoring strategies of HAB spatio-temporal variability in waterbodies are needed. Remote sensing has become an increasingly important tool for HAB detection and monitoring in large lakes. However, accurate HAB detection in small-medium waterbodies via satellite data remains a challenge. Current barriers include the waterbody size, the limited freely available high resolution satellite data, and the lack of field calibration data. To test the applicability of remote sensing for detecting HABs in small-medium waterbodies, three satellites (Planetscope, Sentinel-2 and Landsat-8) were used to understand how spatial resolution, the availability of spectral bands, and the waterbody size itself effect HAB detection skill. Different algorithms and a non-parametric method, Self-Organizing Map (SOM), were tested. Curvature Around Red and NIR minus Red had the best HAB detection skill of the 20 existing algorithms that were tested. Landsat 8 and Sentinel 2 were the best satellites for HAB detection in small to medium waterbodies. The most critical attribute for detecting HABs were the available satellite bands, which determine the detection algorithms that can be used. Importantly, algorithm performance was mostly unrelated to waterbody size. However, there remain some barriers in utilizing satellite data for HAB detection, including algae dynamics, macrophyte cover within the waterbody, weather effects, and the correction models for satellite data. Moreover, it is important to consider the match time between satellite overpass and sampling activities for calibration. Given these challenges, integrating regular sampling activities and remote sensing is recommended for monitoring and managing small-medium waterbodies.

GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells.

Dyskeratosis congenita (DC) is a rare genetic disorder characterized by deficiencies in telomere maintenance leading to very short telomeres and the premature onset of certain age-related diseases, including pulmonary fibrosis (PF). PF is thought to derive from epithelial failure, particularly that of type II alveolar epithelial (AT2) cells, which are highly dependent on Wnt signaling during development and adult regeneration. We use human induced pluripotent stem cell-derived AT2 (iAT2) cells to model how short telomeres affect AT2 cells. Cultured DC mutant iAT2 cells accumulate shortened, uncapped telomeres and manifest defects in the growth of alveolospheres, hallmarks of senescence, and apparent defects in Wnt signaling. The GSK3 inhibitor, CHIR99021, which mimics the output of canonical Wnt signaling, enhances telomerase activity and rescues the defects. These findings support further investigation of Wnt agonists as potential therapies for DC-related pathologies.

The methyltransferase enzymes KMT2D, SETD1B, and ASH1L are key mediators of both metabolic and epigenetic changes during cellular senescence.

Cellular senescence is a terminal cell fate characterized by growth arrest and a metabolically active state characterized by high glycolytic activity. Human fibroblasts were placed in a unique metabolic state using a combination of methionine restriction (MetR) and rapamycin (Rapa). This combination induced a metabolic reprogramming that prevented the glycolytic shift associated with senescence. Surprisingly, cells treated in this manner did not undergo senescence but continued to divide at a slow rate even at high passage, in contrast with either Rapa treatment or MetR, both of which extended life span but eventually resulted in growth arrest. Transcriptome-wide analysis revealed a coordinated regulation of metabolic enzymes related to one-carbon metabolism including three methyltransferase enzymes (KMT2D, SETD1B, and ASH1L), key enzymes for both carnitine synthesis and histone modification. These enzymes appear to be involved in both the metabolic phenotype of senescent cells and the chromatin changes required for establishing the senescence arrest. Targeting one of these enzymes, ASH1L, produced both a glycolytic shift and senescence, providing proof of concept. These findings reveal a mechanistic link between a major metabolic hallmark of senescence and nuclear events required for senescence.

Patient preferences pertaining to treatment options for drug-resistant focal epilepsy.

OBJECTIVE: To determine patient acceptability of benefit-risk trade-offs in selecting treatment options for drug-resistant mesial temporal lobe epilepsy, including open brain surgery, laser ablation (laser interstitial thermal therapy [LITT]), and continued medications. METHODS: A discrete-choice experiment survey was developed, consisting of 20 versions that were randomly assigned to respondents. Each version had 8 sets of constructed treatment alternatives, representing open brain surgery, LITT, or continued medical management. For each set, respondents indicated the treatment alternative they would choose first. Treatment alternatives were characterized by varying levels of chance of seizure freedom for at least 2 years (20-70%), risk of 30-day mortality (0-10%), and risk of neurological deficits (0-40%). Respondents' choices were analyzed using random-parameters logit models to quantify acceptable benefit-risk trade-offs. Preference heterogeneity was evaluated using latent-class analysis. RESULTS: The survey was administered to 2 cohorts of adult patients with drug-resistant epilepsy: a Duke cohort identified using diagnostic codes (n = 106) and a web-recruited panel with a self-reported physician diagnosis of drug-resistant epilepsy (n = 300). Based on mean preference weights, respondents who indicated a willingness to consider surgical intervention would accept a reduction in chance of seizure freedom from 70% to a minimum-acceptable benefit (MAB) of 23% if they could undergo LITT rather than open brain surgery. For a reduction in 30-day mortality from 1% to 0%, MAB was 52%. For a reduction in risk of long-term deficits from 10% to 0%, MAB was 39%. Latent-class analysis revealed additional choice patterns identifying respondent groups that more strongly favored continuing medications or undergoing surgery. CONCLUSION: Patients who are receptive to surgery would accept significantly lower treatment effectiveness to undergo a minimally invasive procedure relative to open brain surgery. They also were willing to accept lower treatment benefit to reduce risks of mortality or neurological deficits.

Quantifying Benefit-Risk Preferences for Heart Failure Devices: A Stated-Preference Study.

BACKGROUND: Regulatory and clinical decisions involving health technologies require judgements about relative importance of their expected benefits and risks. We sought to quantify heart-failure patients' acceptance of therapeutic risks in exchange for improved effectiveness with implantable devices. METHODS: Individuals with heart failure recruited from a national web panel or academic medical center completed a web-based discrete-choice experiment survey in which they were randomized to one of 40 blocks of 8 experimentally controlled choice questions comprised of 2 device scenarios and a no-device scenario. Device scenarios offered an additional year of physical functioning equivalent to New York Heart Association class III or a year with improved (ie, class II) symptoms, or both, with 30-day mortality risks ranging from 0% to 15%, in-hospital complication risks ranging from 0% to 40%, and a remote adjustment device feature. Logit-based regression models fit participants' choices as a function of health outcomes, risks and remote adjustment. RESULTS: Latent-class analysis of 613 participants (mean age, 65; 49% female) revealed that two-thirds were best represented by a pro-device, more risk-tolerant class, accepting up to 9% (95% CI, 7%-11%) absolute risk of device-associated mortality for a one-year gain in improved functioning (New York Heart Association class II). Approximately 20% were best represented by a less risk-tolerant class, accepting a maximum device-associated mortality risk of 3% (95% CI, 1%-4%) for the same benefit. The remaining class had strong antidevice preferences, thus maximum-acceptable risk was not calculated. CONCLUSIONS: Quantitative evidence on benefit-risk tradeoffs for implantable heart-failure device profiles may facilitate incorporating patients' views during product development, regulatory decision-making, and clinical practice.

What is a Good Death? A Choice Experiment on Care Indicators for Patients at End of Life.

CONTEXT: Health systems should aim to deliver on what matters most to patients. With respect to end of life (EOL) care, knowledge on patient preferences for care is currently lacking. OBJECTIVES: To quantify preference weights for key EOL care indicators. METHODS: We developed a discrete choice experiment survey with 13 key indicators related to patients' experience in the last six weeks of life. We fielded the survey to a web-panel of caregiver proxies for recently deceased care recipients. We obtained 250 responses in each of five countries: India, Singapore, Kenya, the UK and the US. Latent-class analysis was used to evaluate preference weights for each indicator within and across countries. RESULTS: A 2-class latent-class model was the best fit. Class 1 (average class probability = 64.7%) preference weights were logically ordered and highly significant, while Class 2 estimates were generally disordered, suggesting poor data quality. Class 1 results indicated health care providers' ability to control patients' pain to desired levels was most important (11.5%, 95% CI: 10.3%-12.6%), followed by clean, safe, and comfortable facilities (10.0%, 95% CI: 9.0%-11.0%); and kind and sympathetic health care providers (9.8%, 95% CI: 8.8%-10.9%). Providers' support for nonmedical concerns had the lowest preference weight (4.4%, 95% CI: 3.6%-5.3%). Differences in preference weights across countries were not statistically significant. CONCLUSION: Results reveal that not all aspects of EOL care are equally valued. Not accounting for these differences would lead to inappropriate conclusions on how best to improve EOL care.